First, how does radiation work?

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1 Hello, I am Prajnan Das, Faculty Member in the Department of Radiation Oncology at The University of Texas MD Anderson Cancer Center. We are going to talk today about some of the basic principles regarding radiation therapy. We will talk about the biologic effects of radiation, how radiation works. We will discuss the steps involving radiation therapy planning, and we will talk about some clinical applications and complications associated with radiation therapy. First, how does radiation work? There are two kinds of radiation non-ionizing and ionizing. Non-ionizing radiation consists of particles that do not have enough energy to produce ions in matter, such as microwaves, ultrasound, and radio waves. Since these kinds of radiation do not produce ions in matter, their biologic effects can be limited. In contrast, ionizing radiation is able to eject orbital electrons and produce ions. There are two kinds of ionizing radiation. Directly ionizing, these are charged particles, such as electrons, protons, and alpha particles; and indirectly ionizing, and these are uncharged particles, such as neutrons, gamma rays, and x-rays. Ionizing radiation leads to ionizations. The ionizations then go on to produce free radicals in tissue and the free radicals cause DNA damage, and the DNA damage leads to the biologic effects of ionizing radiation. How does radiation damage DNA? The free radicals can produce strand breaks in the DNA. When strand breaks are produced in a single strand of DNA, the single strand breaks can be repaired easily. But when strand breaks are produced in both strands, these double strand breaks can be difficult to repair. Hence double strand breaks are the most important lesion produced by radiation. Double strand breaks can lead to cell death, mutation, or carcinogenesis. And these double strand breaks can affect both tumor and normal tissue. Since radiation can affect both tumor and normal tissue, the goal of a radiation oncologist is to maximize damage to the tumor cells, but minimize damage to normal tissues. The way we measure radiation dose is in terms of energy imparted by ionizing radiation per unit mass of matter. The unit of radiation is a Gray (Gy), and a Gray is one Joule of radiation delivered per kilogram of matter. Another commonly used unit is a centigray (cgy) and 1 Gy equals 100 cgy. Radiation is often not given in a single dose but given in a number of smaller doses spread over several days. This process of dividing the radiation dose into a number of smaller doses or fractions is known as fractionation. The biologic basis of fractionation are the four R s : repair of DNA damage, repopulation of cells, reassortment into cell cycle and reoxygenation. And these biologic processes affect the effect of radiation when it is given over several fractions. For example, a lower total dose in large

2 fractions can have the same biologic effect as a higher total dose given in small fractions over a longer time period. Similarly, single fractions of radiation can have completely different effects compared to multiple fractions given daily. There are a number of factors that can affect the biologic effects of radiation. The type of radiation is important, and this can depend on the density of ionizations produced by that kind of radiation. The dose rate of radiation is important, whether you are giving radiation at a slower rate or at a faster rate. The type of tissue is important. In general, you can divide tissues into early responding tissues and late responding tissues. Early responding tissues typically include rapidly proliferating cells, such as skin and gastrointestinal mucosa. And these tend to be more sensitive to radiation and also exhibit damage from radiation early in the time course. Late responding tissues typically include cells that do not proliferate at a fast rate, such as neurons or renal cells. And these tend to be more resistant to radiation and exhibit damage from radiation at a later point in time. As we discussed earlier, for DNA damage to take place from radiation, you need free radicals, and free radical production requires oxygen. Hence, the level of oxygenation in a tissue can affect the role of radiation. And hypoxic cells tend to be less sensitive to radiation. A number of agents can be used for radiosensitization, such as chemotherapeutic agents, 5-FU, cisplatin, and biologic agents such as cetuximab. And these have been shown to enhance the effects of radiation in randomized trials. The overall treatment time is also important. Hence, if gaps are introduced in the middle of a patient s radiation therapy course, the therapeutic effects of radiation may be diminished. So far, we have been talking about how radiation works. Next, we are going to be talking about how radiation is given. The first step in the radiation planning process is simulation. For radiation simulation, the patient has to be positioned. We have to decide whether to position the patient prone or supine, what position the arms or legs have to be in. And the patient then gets immobilized with devices, such as thermoplastic masks for the head and neck, cradles for the body, and these allow us to place the patient in the same position every day in a reliable and reproducible manner. Once the patient is positioned, the patient gets imaged. In the past, fluoroscopy was used, but this has largely been replaced by CT scans now. The photo here shows an example of a CT scan used for radiation simulation. A number of newer techniques have been introduced in the simulation process. Image fusion can be used to fuse head images and MR images with CT images so that the target can be delineated more accurately. 4-D CT images can be used to track motion of a tumor and normal structures over time while the patient breathes. And this can be important for organs such as the lungs and the liver which move when a patient breathes. Once a patient is positioned and imaged, reference marks are placed on the patient using ink marks or tattoos, and the patient can be lined up to these every day for treatment. The next step in the radiation planning process is treatment planning. This involves the radiation oncologist going through the CT images slice by slice and outlining the

3 radiation targets and other organs on every slice. This process is called contouring. Once the targets are delineated through the contouring process, we have to design the beam arrangement. We have to decide how many beams we will use, what size the beams are going to be, and what their orientation or angles are going to be. Then each beam can be shaped using blocks so that the target is treated, but normal structures are protected. Blocks can be made with a lead-containing material called Cerrobend. Nowadays, fields are typically blocked using multi-leaf collimators which are thick leaves in the head of a radiation treatment machine that can move in and out of the field, thus shaping the field. Once a patient goes through simulation and treatment planning, we are now ready to treat the patient. A variety of treatment machines can be used. In the past, radiation was most commonly delivered using Cobalt-60, which is an isotope that generates radiation. Cobalt-60 is still widely used in developing countries. In the developed world, Cobalt-60 is commonly used in gamma ray machines for stereotactic treatments. However, the most common method of delivering external beam radiation therapy is by using linear accelerators. The photo here shows an example of a linear accelerator used to deliver radiation therapy. Linear accelerators can generate two different kinds of radiation, photons and electrons, and these have different clinical applications. Next, we will go through a case study that illustrates the steps of radiation planning that we have been talking about. The patient here is a 66-year-old man who had resectable pancreatic cancer. After multidisciplinary discussion, we recommended pre-operative chemoradiation followed by surgery. We used a CT-based simulation technique. The patient was placed in a supine position with his arms up. A body cradle was used for immobilization, and then CT images of the abdomen were obtained. We then went through the CT images slice-by-slice and outlined the tumor, surrounding lymph nodes regions, and normal structures, such as the kidneys, liver and spinal cord. We decided to treat this patient with a 4-field technique: anterior, posterior, and two lateral fields. The figure on the left shows the anterior field and the figure on the right shows the lateral field used to treat this patient. The large red structure in the middle of the field shows the pancreatic tumor. The other colored structures show other lymph node regions that were included in the target. The red and blue boxes show the actual radiation fields, and the white stripes show the multi-leaf collimators that were used to block parts of the field and shape the field. Once the fields are designed, we can evaluate the radiation plan using isodose curves. We obtain isodose curves for each slice of the CT scan and want representative slices shown here. Each isodose line represents a particular dose of radiation therapy. In this case, the prescription dose was 5040 cgy as shown by the white line. As you can see, the tumor is being adequately covered by the white line. In contrast, normal structures, such as the bowel, liver, and kidneys, are getting much lower doses of radiation. You can quantify doses received by the target and normal structures using a DVH or Dose Volume Histogram. In this figure, the x-axis shows the radiation dose, and the y-

4 axis shows the proportion of each organ that is receiving that dose. As you can see from the green line on the top, the tumor and the targeted lymph nodes, 100% of those are getting the prescribed dose of 5040 cgy. The dose to the spinal cord is shown in red. The maximum dose the spinal cord can tolerate is 45 Gy. As you can see, no part of the spinal cord is getting more than 30 Gy. The orange line shows dose to the liver. The tolerance dose for the liver is 30 Gy. As you can see, less than 10% of the liver is getting more than 30 Gy. Similarly, the kidneys are also within the acceptable tolerance limits. Radiation therapy can also be delivered using IMRT which stands for Intensity Modulated Radiation Therapy. IMRT uses computers to optimize the radiation plan. Multiple beams are used, and these beams are shaped with multi-leaf collimation in complex patterns. This allows us to deliver highly conformal radiation therapy to the target, but minimize dose to surrounding normal tissues. IMRT also allows dose painting so that different areas of a target can be treated with different prescribed doses. As I mentioned, IMRT uses multiple beams shaped in complex manners as shown by these radiographs. This is an example of a patient treated with IMRT for squamous cell anal cancer. The red structure represents the primary tumor which is being treated to a dose of 54 Gy as shown by the red line. An involved lymph node is shown by the blue structure which is being treated with a dose of 50 Gy as shown by the blue line. Other lymph node regions shown by the green --- shown in green are being treated with a dose of 45 Gy as shown by the green line. Note that the radiation dose lines are bending away from critical structures, such as the bowel, genitalia, and femoral heads. Thus, IMRT allows us to treat the target but spare normal tissues in a manner that cannot be always achieved using conventional treatment plans. Another exciting innovation in the field of radiation therapy is proton therapy. Protons are charged particles with special physical properties that are different from that of photons, which is what we typically use in using our linear accelerators. In the figure, the x-axis shows the depth from the surface into the body of a patient, and the y-axis shows relative radiation dose. The green line shows dose distribution from a 15 megavoltage photon beam. As you can see, near the skin surface there is some sparing, but then the dose peaks and then falls gradually. So if you needed to treat a tumor, say at a depth of 20 cm, regions that are right behind it and right ahead of it would get similar doses of radiation. In contrast, a proton beam behaves very differently as shown by the red line. As you can see, there is a certain entrance dose, but then the dose rises up very rapidly and dose gets deposited within a short distance known as the Bragg peak. Beyond the Bragg peak, the dose falls off abruptly and there is minimal dose beyond the Bragg peak. This allows us to treat an organ while delivering minimal dose to surrounding normal structures.

5 Most of the examples of radiation that we have talked about so far involve teletherapy or external beam radiation therapy. Another way of delivering radiation therapy is brachytherapy. Brachy means short distance. In brachytherapy, the radioactive material, radioisotopes, are placed within the body, either within a body cavity or within the tissues. The radiation dose decreases rapidly with distance from the radioactive material, and this allows us to treat the tumor to a high dose, but spare surrounding normal structures. The radiograph here shows an example of a prostate cancer patient treated with brachytherapy. The little gray specks within the prostate show individual radiation seeds that were placed into the prostate to treat this patient. In the last section, we are going to discuss some clinical issues pertinent to radiation therapy. Radiation therapy can have a variety of roles in the care of a cancer patient. Radiation therapy can be used for primary treatment in the definitive setting, such as for prostate cancer, lung cancer, head and neck cancer, cervical cancer, and anal canal cancer. And for many of these cancers, radiation is given concurrently with chemotherapy. Radiation therapy can be used for post-operative treatment for breast cancer and stomach cancer, for pre-operative treatment of rectal and esophageal cancer. Radiation therapy is used for consolidation after chemotherapy for many lymphomas. And radiation can also be used for palliation of symptoms. It is important to keep in mind that there are certain indications for urgent radiation therapy, and these patients need to be referred to a radiation oncologist on an emergent basis. Examples include spinal cord compression, brain metastasis with symptoms, SVC syndrome with progressive symptoms, uncontrolled bleeding, or peripheral nerve involvement with symptoms. Radiation can cause a variety of complications or side effects. These complications mainly occur locally in organs that are in the radiation field. Some complications can occur during treatment or within days or weeks while some complications can be long term and can appear after months or years. Examples of complications include fatigue, skin toxicity such as erythema and desquamation. Radiation to the brain can lead to somnolence or cognitive loss. That to the head and neck area could potentially lead to mucositis and xerostomia. Radiation to the lung can cause pneumonitis; to the upper GI can lead to nausea and esophagitis; and to the lower GI can lead to diarrhea and proctitis. Radiation therapy to the genitourinary system can cause cystitis, urethritis or sexual dysfunction. Radiation can also cause myelosuppression. Two of the most important long-term side effects of radiation include cardiovascular toxicity and second malignancies. What is the role of a radiation oncologist? A radiation oncologist evaluates whether a particular patient is appropriate for radiation. And in doing so, the radiation oncologist functions as an integral part of the multidisciplinary oncology team. Next, the radiation oncologist plans and delivers radiation therapy. This is a team effort and the radiation

6 oncologist is aided by physicists, dosimetrists, and radiation therapists. Radiation oncologists help treat symptoms and side effects of radiation and also monitors these patients in the long term for relapses and long-term toxicity. Finally, the radiation oncologist performs specialized procedures, such as brachytherapy and intraoperative radiation therapy. In conclusion, we have discussed today that radiation has an --- is an important treatment modality for the management of cancer. The treatment planning process includes simulation, contouring targets, and designing beam arrangements. Specialized radiation techniques include Intensity Modulated Radiation Therapy, Proton Therapy, and Brachytherapy. We have also discussed some clinical issues relevant to radiation therapy. Thank you for your attention.